The present invention relates to a method of determining the susceptibility of a non-insulin-dependent diabetes mellitus (NIDDM) patient toward a sulfonylurea therapy.
Sulfonylureas are oral hypoglycaemic agents widely used in the treatment of NIDDM. They bind to the high affinity sulfonylurea receptor 1 (SUR1) and stimulate insulin release from pancreatic islet xcex2 cells. SUR1 is one of the protein that composes the ATP-sensitive potassium channel IKATP, closed by glucose metabolism in pancreatic xcex2 cells and triggering insulin exocytosis. The gene encoding SUR1 is located on chromosome 11p15.1. Mutations in the gene have been found in Familial Persistent Hyperinsulinemic Hypoglycaemia of Infancy (PHHI) (Thomas et al, (1995); Thomas et al (1986), Kane et al (1996) and Dunne et al (1997)) also known as Familial Hypersinsulinism (HI) (Nestorowicz et al (1996)). This disease is characterized by the elevation of serum insulin levels and severe hypoglycaemia.
Two case-control studies reported an association between genetic polymorphisms in the SUR1 gene and NIDDM. (Inoue et al, (1996) Hansen et al (1998)). To estimate the impact of the SUR1 genetic variability on NIDDM in population, the inventors characterized the genotypes of subjects for the most frequent polymorphism of the SUR1 gene, a xe2x88x923cxe2x86x92t mutation located in intron 15, namely in position xe2x88x923 of the exon 16 splice acceptor site (nucleotide 191 of SEQ ID nxc2x0 1) in a large representative sample of the French population aged 35 to 64 years.
As a result, they discovered that among the NIDDM patients, the frequency of the t allele was significantly lower in controls than in NIDDM patients.
In controls, no association was found between the polymorphism and body mass index, waist-to-hip ratio, fasting plasma glucose, fasting plasma insulin and lipid and lipoproteins profile. In NIDDM patients, the t allele was associated with a decrease in plasma triglycerides concentrations. NIDDM patients were stratified in two groups:subjects treated with sulfonylureas and subjects treated without. Decreases in plasma triglycerides and VLDL-cholesterol concentrations were found only in t allele bearers treated with sulfonylureas.
The present invention concerns the discovery that sulfonylurea therapy seems to be more efficient on hypertriglyceridemia reduction in NIDDM patients with the SUR1 intron 15 t allele than in NIDDM patients without, which may help to better target various therapies available in NIDDM treatment.
The present invention relates to a method for determining the susceptibility of a NIDDM patient toward sulfonylurea therapy comprising:
obtaining a sample from a NIDDM patient, said sample comprising nucleic acid molecules containing the fragment of the SUR1 gene comprising the nucleotide in position xe2x88x923 of exon 16,
detecting the presence or the absence of the xe2x88x923 t allele in position xe2x88x923 of exon 16,
whereby the presence of at least one xe2x88x923 t allele identifies a NIDDM patient with a higher susceptibility toward sulfonylurea therapy.
Sulfonylurea therapy in the sense of the instant invention identifies the current therapies of NIDDM utilizing oral hypoglycaemic agents binding the SUR1 receptor and stimulating insuline release from pancreatic islet xcex2 cells.
Such agents are derivatives of arylsulfonylurea having the following general formula: 
wherein R1 may have the following meanings: Cl, CH3, 
and R2 may have the following meanings:
xe2x80x94(CH2)2CH3
xe2x80x94(CH2)3CH3
The main compounds are known under the following denominations: chlorpropamide, tolbutamide, gliclazide, glibomuride, glibenclamide, glipizide and buformine.
The sample from the patient may be any biological sample containing nucleic acids, namely a blood sample.